This application for continuation of the Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancer at the Johns Hopkins Medical Institutions supports a highly interactive, multidisciplinary, and interinstitutional program. Eight research projects within four research programs, four cores, a career development and a research developmental program are proposed to further our translational research in colorectal and pancreatic cancer. Research Program 1: Applied Cancer Genetics (0012, Diagnosis and prognosis of human cancers through molecular genetic analyses, Dr. Kenneth Kinzler; 0002, New genetic clues in pancreatic cancer, Dr. Scott Kern). Program 2: Markers of Tumorigenesis (0013, Components of early and late pancreatic neoplasia, Dr. Scott Kern; 0008, Screening markers for high pancreatic cancer susceptibility, Dr. Michael Goggins). Program 3: Assessment of Familial Risk- (0014, Risk prediction in familial colorectal cancer, Dr. Giovanni Parmigiani; 0011, Markers for risk in familial pancreatic cancer, Dr. Ralph Hruban). Program 4: Therapeutic Directions (0015, Chemoprevention of human colorectal tumors, Dr. David Huso; 0016, Integration of chemotherapy with vaccination in metastatic pancreatic cancer, Dr. Elizabeth Jaffee). The cores support the research programs ( 9002, Human Tissue Research and Logistics, Dr. Elizabeth Montgomery; 9003, Familial Cancer Registries, Dr. Frank Giardiello; 9004, Statistics/Bioinformatics, Dr. Steven Goodman. The Career Development Program (Dr. Scott Kern) aids the emergence of new investigators and the Research Developmental Program (Dr. Bert Vogelstein) provides rapid funding of innovative directions.